The immature brain is more susceptible to seizures than later in life, and early life epilepsy is often associated with cognitive comorbidities. The link between seizures and cognitive deficits is not understood. Our lab has found that molecular pathways affected by seizures in the hippocampus overlap with mechanisms involved in cognition, with a potential convergence on calcium (Ca2+) signaling in synaptogenesis and synaptic plasticity. First, seizures down-regulate the GluR2 subunit of a-amino-3- hydroxy-5-methylisoxasole-4-propionic acid (AMPA) receptors, potentially allowing more Ca2+ to enter the cell. Hypoxic seizures alter expression and phosphorylation of Ca2+-dependent signaling molecules central to synaptic plasticity. Also, seizures cause long-lasting changes in hippocampal neuronal network excitability and occlude long-term potentiation (LTP), a cellular correlate for learning. I hypothesize that Ca2+-mediated signaling cascades are central to the pathophysiology of epileptogenesis and comorbid cognitive defects that follow early life seizures. The objective of the work outlined here is to examine Ca2+ signaling as a functional convergence point of epilepsy and cognitive dysfunction, clarify the mechanisms altered during epileptogenesis, and provide a basis for future studies specifically targeting these pathways in vivo. The broad goal is to devise therapeutic strategies to block development of cognitive deficits during epileptogenesis. In Aim 1, I will determine whether seizures in the immature brain alter AMPA receptor- mediated Ca2+ influx in hippocampal CA1 pyramidal neurons by measuring changes in Ca2+ responses with ratiometric Ca2+ imaging in acute slices. I hypothesize that GluR2 subunit down-regulation increases neuronal Ca2+ influx within hours of hypoxia, and persists into adulthood. In Aim2, 1 will determine if changes in plasticity seen after hypoxic seizures are linked to changes in Ca2+ by using whole cell recordings in parallel with Ca2+ imaging in acute hippocampal slices from rats following seizures and will compare Ca2+ responses to those of age-matched controls. I hypothesize that seizures alter levels of neuronal Ca2+ entry, partially occluding LTP in the neuronal network, rendering cells less "plastic". Relevance: Seizures often accompany autism-spectrum disorders but the direct effects of seizures on cognition are unknown. Studies proposed here examine the interaction between seizures and memory at the cellular level by assessing changes in calcium signaling after seizures and how these changes affect cellular correlates of learning. The broad goal of this work is to provide potential therapeutic targets to block development of cognitive deficits during epileptogenesis.